Effect of Multiple Doses of Modafinil on the Pharmacokinetics of Single Dose Lorlatinib in Healthy Participants

This will be a Phase 1 study in approximately 16 healthy participants employing administration of a single dose of lorlatinib in the fasted state alone, and with multiple doses of modafinil 400 mg once daily. This study will consist of up to 3 lorlatinib treatment groups: 50, 75, or 100 mg single doses of lorlatinib given alone and in combination with multiple doses of modafinil.

Each enrolled participant will receive lorlatinib 50, 75, or 100 mg alone in Period 1 and then lorlatinib 50, 75, or 100 mg in combination with multiple dose modafinil in Period 2 after a washout period of at least 19 days between lorlatinib doses in Periods 1 and 2. A single PK sample is taken prior to lorlatinib dosing in each period. Following administration of lorlatinib in each period, participants will undergo serial PK sampling.

There will be 4 cohorts. Cohorts 1 to 3 will include 2 participants each, while Cohort 4 will include 10 participants. Participants in Cohorts 1 to 4 will be sequentially enrolled such that participants in a new cohort can receive their lorlatinib Period 2 dose only after participants from the prior cohort are 72 hours past their lorlatinib Period 2 combination dose (with modafinil) with no safety concerns. In addition, Cohorts 1 to 3 will employ sentinel dosing such that the second participant in each cohort can receive their lorlatinib Period 2 dose only after the first participant from the same cohort is 72 hours past their lorlatinib and modafinil Period 2 combination dose with no safety concerns. Participants in Cohort 4 may be dosed in parallel, as sentinel dosing of lorlatinib 100 mg will have been completed in Cohort 3. The overall study design will be identical in all 4 cohorts, with the only difference being the dose of lorlatinib administered.

The decision to dose subsequent cohorts during Period 2 with lorlatinib will be made after reviewing the totality of the participants' clinical picture for safety by the investigator. Furthermore, participants in subsequent cohorts will not be dosed if the following liver function abnormalities are observed during the 72 hour time frame for safety evaluation after lorlatinib dosing in Period 2.

For enrollment of each successive cohort, the period of safety evaluation will be at least 72 hours after the Period 2 lorlatinib dosing in the previous cohort. During Period 2, safety laboratory assessments including urinalysis, hematology and chemistry will be performed once daily from Day 14 through Day 20. Only after the review of safety labs for at least 72 hours after lorlatinib+ modafinil dosing during Period 2 of the previous cohort, will participants in a new cohort receive lorlatinib in combination with modafinil in their Period 2. Additional safety laboratory assessments may be performed at any additional times at the discretion of the investigator. If safety events of concern are observed in Cohorts 1, 2, or 3 during Period 2, this study will be terminated.

Inclusion criteria

• Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and ECG.
• Adequate Renal Function, including:

Estimated creatinine clearance ≥90 mL/min as calculated using chronic kidney disease epidemiology collaboration equation (CKD EPI). In equivocal cases, a 24 hour urine collection test can be used to estimate the creatinine clearance more accurately.

• Adequate Liver Function, including: Total serum bilirubin within normal limits (WNL). Aspartate and Alanine aminotransferase (AST and ALT) WNL. Alkaline phosphatase WNL.

• Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
• Male participants of childbearing potential must agree to use a highly effective method of contraception from the first screen throughout the study and for 97 days after the last dose of assigned treatment if male participant. A participant is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
• Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).
• Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this

Exclusion criteria

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
• Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
• History of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C; positive testing for HIV, hepatitis B surface antigen (HepBsAg), or hepatitis C antibody (HCVAb). A positive hepatitis B surface antibody (HepBsAb) serology indicating Hepatitis B vaccination is allowed.
• Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. Psychiatric adverse experiences have been reported in patients treated with modafinil with many, but not all, with prior psychiatric history. Participants with a history of psychosis, depression, or mania are excluded from this study.
• Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of investigational product. As an exception, acetaminophen/paracetamol may be used at doses of ≤1 g/day. Limited use of nonprescription medications that are not believed to affect participant safety or the overall results of the study may be permitted on a case by case basis following approval by the sponsor.
• Previous administration with lorlatinib within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of lorlatinib used in this study (whichever is longer).
• Previous treatment with lorlatinib
• A positive urine drug test, as confirmed by a single repeat.
• Screening supine blood pressure (BP) ≥130 mm Hg (systolic) or ≥80 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is ≥130 mm Hg (systolic) or ≥80 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility.
• History of pancreatitis (elevated amylase or lipase) or hyperlipidemia.
• Screening supine 12 lead ECG demonstrating PR interval >200 msec, corrected QT (QTc) >450 msec or a QRS interval >120 msec.
• History of cardiac arrhythmia (excluding asymptomatic sinus arrhythmia with heart rate >50, and occasional asymptomatic premature atrial contraction and premature ventricular contractions), history of atrioventricular (AV) block, history of symptomatic bradycardia, history of QTc prolongation.
• Participants with ANY of the following abnormalities in clinical laboratory tests at screening: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level > upper limit of normal (ULN); Total bilirubin level > ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is ≤ ULN.
• History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week for males or 7 units per week for females (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
• As modafinil is a controlled substance, participants with a history drug abuse will be excluded.
• Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing.
• History of sensitivity to lorlatinib or modafinil.
• Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of this protocol.
• Male participants with partners currently pregnant; male participants able to father children who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 97 days after the last dose of investigational product or longer based upon the compound's half life characteristics, and refrain from sperm donation for the duration of the study and for at least 97 days after the last dose of investigational product.
• Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Pfizer employees, including their family members, directly involved in the conduct of the study.